Racetams are a class of drugs that share a pyrrolidone nucleus. [1] Some, such as piracetam, aniracetam, oxiracetam, pramiracetam and phenylpiracetam are considered nootropics. [2] Others such as levetiracetam, brivaracetam, and seletracetam are anticonvulsants.
There is no universally accepted mechanism of action for racetams. Racetams generally show negligible affinity for common central nervous system receptors, but modulation of central neurotransmitters, including acetylcholine and glutamate, has been reported. Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam demonstrates nanomolar interactions. Modification of membrane-located mechanisms of central signal transduction is another hypothesis. [3]
Like some ampakines, some racetams, such as piracetam and aniracetam, are positive allosteric modulators of the AMPA receptor. [4]
Racetams are understood to work by allosterically modulating glutamate receptors, specifically AMPA receptors, leading to Ca2+ influx that is excitatory. [5] Racetams are posited to enhance memory through interaction with glutamate receptors in the central nervous system.
Methylphenylpiracetam is a positive allosteric modulator of the sigma-1 receptor. [6]
In studies with aged rats, marked improvement has been observed in cognitive tasks in experimental groups given piracetam. Performance was further increased when piracetam was combined with choline. Evidence in studies with rats has indicated that the potency of piracetam is increased when administered with choline. [7]
| Structure | Name |
|---|---|
 | Piracetam |
 | Oxiracetam |
 | Phenylpiracetam / Fonturacetam |
 | Phenylpiracetam Hydrazide / Fonturacetam Hydrazide |
 | Aniracetam |
 | Pramiracetam |
 | Seletracetam |
 | Levetiracetam |
 | Coluracetam / BCI-540 |
 | Fasoracetam |
 | Brivaracetam |
 | Dimiracetam |
 | Methylphenylpiracetam / E1R |
 | Nebracetam |
 | Nefiracetam |
 | Omberacetam / Noopept |
 | Rolziracetam |
 | Cebaracetam |
All racetams are schedule 4 substances in Australia under the Poisons Standard (February 2020). [8] A schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription." [8]
Nootropics are numerous natural, semi-synthetic and synthetic molecules which purportedly improve cognitive functions.
Piracetam is a drug marketed as a treatment for myoclonus. It is also used as a cognitive enhancer to improve memory, attention, and learning. Evidence to support its use is unclear, with some studies showing modest benefits in specific populations and others showing minimal or no benefit. Piracetam is sold as a medication in many European countries. Sale of piracetam is not illegal in the United States, although it is not regulated nor approved by the FDA so it is legally sold for research use only.
Aniracetam, also known as N-anisoyl-2-pyrrolidinone, is a racetam which is sold in Europe as a prescription drug. It is not approved by the Food and Drug Administration for use in the United States as a prescription medication or dietary supplement. Despite the FDA's lack of approval, the drug is readily available over-the-counter in misbranded dietary supplements.
Oxiracetam is a nootropic drug of the racetam family and a very mild stimulant. Several studies suggest that the substance is safe even when high doses are consumed for a long period of time. However, the mechanism of action of the racetam drug family is still a matter of research. Oxiracetam is not approved by Food and Drug Administration for any medical use in the United States.
Coluracetam is a purported nootropic agent of the racetam family. It is contains a chemical group that is a bioisostere of the 9-amino-tetrahydroacridine family. It was initially developed and tested by the Mitsubishi Tanabe Pharma Corporation for Alzheimer's disease. After the drug failed to reach endpoints in its clinical trials it was in-licensed by BrainCells Inc for investigations into major depressive disorder (MDD), which was preceded by being awarded a "Qualifying Therapeutic Discovery Program Grant" by the state of California. Findings from phase IIa clinical trials have suggested that it would be a potential medication for comorbid MDD with generalized anxiety disorder (GAD). BrainCells Inc is currently out-licensing the drug for this purpose. It may also have potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury.
Ampakines or AMPAkines are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (AMPAR), a type of ionotropic glutamate receptor with which the ampakines interact and act as positive allosteric modulators (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines.
Phenylpiracetam, is a phenylated analog of the drug piracetam. It was developed in 1983 as a medication for Soviet Cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina. In Russia it is now available as a prescription drug. Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anticonvulsant, anxiolytic, and memory enhancement effects.
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].
IDRA-21 is a positive allosteric modulator of the AMPA receptor and a benzothiadiazine derivative. It is a chiral molecule, with (+)-IDRA-21 being the active form.
LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly.
PEPA is a sulfonamide AMPA receptor positive allosteric modulator, which is up to 100 times more potent than aniracetam in vitro. It produces memory-enhancing effects in rats when administered intravenously.
LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators.
Sunifiram is an experimental drug which has antiamnesic effects in animal studies and with significantly higher potency than piracetam. Sunifiram is a molecular simplification of unifiram (DM-232). Another analogue is sapunifiram (MN-19). As of 2016, sunifiram had not been subjected to toxicology testing, nor to any human clinical trials, and is not approved for use anywhere in the world.
Unifiram is an experimental drug. that has antiamnesic and other effects in animal studies with far greater potency than piracetam. A number of related compounds are known, such as sunifiram (DM-235) and sapunifiram (MN-19). Unifiram has two enantiomers, with the dextro form being the more active isomer. It has been shown to reduce the duration of hypnosis induced by pentobarbital, without impairing motor coordination. As of 2015, no formal human studies with unifiram have been conducted. Unifiram is not patented and, despite the lack of human and long-term toxicity studies, it is commonly sold online.
Pregnenolone sulfate is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.
S-18986 is a positive allosteric modulator of the AMPA receptor related to cyclothiazide. It has nootropic and neuroprotective effects in animal studies, and induces both production of BDNF and AMPA-mediated release of noradrenaline and acetylcholine in the hippocampus and frontal cortex of the brain.
Methylphenylpiracetam is a derivative of piracetam and a positive allosteric modulator of the sigma-1 receptor. It differs from phenylpiracetam by having a methyl group.
Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. As of July 2018, pesampator is in phase II clinical trials for cognitive symptoms in schizophrenia.
Mibampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Eli Lilly for the treatment of agitation/aggression in Alzheimer's disease but was never marketed. It reached phase II clinical trials prior to the discontinuation of its development.
AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.
The R-configuration enantiomers of methylphenylpiracetam are more active positive allosteric modulators of Sigma-1 receptor than S-configuration enantiomers.